In recent years, by virtue of its biological activity, an antisense oligonucleotide containing, as a constituent, 2′-deoxy-2′-fluoro-β-D-arabinonucleoside (2′F-ANA) has become more attractive (Patent Document 1 and Non-Patent Documents 1 and 2).
2′F-ANA is a known compound, and methods for chemically synthesizing the compound have already been reported (Patent Document 2 and Non-Patent Documents 3 and 4). Specifically, since 2′F-ANA is difficult to derive from natural nucleosides, 2′F-ANA is synthesized through substitution reaction (condensation reaction) between a 1-halogenated sugar derivative and a base of nucleic acid. However, the resultant reaction mixture contains the α-isomer of the arabinonucleoside in addition to the β-isomer thereof, and thus production of highly pure 2′F-ANA requires a purification process employing, for example, an intricate column chromatography.
Of species of 2′F-ANA, 2′-deoxy-2′-fluoro-β-D-arabinopyrimidinenucleoside can be synthesized relatively easily. In contrast, no efficient method for synthesizing 2′-deoxy-2′-fluoro-β-D-arabinopurinenucleoside has yet been established, since the reaction mixture contains a variety of isomers (e.g., α-isomer, β-isomer, 7-substituted isomer, and 9-substituted isomer).
Enzymatic synthesis methods have been proposed as one means for overcoming drawbacks involved in the aforementioned chemical synthesis methods. For example, there has been proposed a method in which an α-1-phosphorylated sugar derivative is synthesized by shifting the isomerization equilibrium of 1-phosphorylated-2-deoxyribose products, followed by employment of a nucleoside phosphorylase, to thereby produce a target nucleoside (Patent Document 3).
However, the present inventors have found that 1-phosphorylated-2-deoxy-2-fluoroarabinoside is relatively stable, and the equilibrium of the α-isomer and β-isomer of the fluoroarabinoside is difficult to shift to one direction, and therefore difficulty is encountered in applying the aforementioned enzymatic synthesis method to production of 2′F-ANA.
Also, there has been reported a method for enzymatically synthesizing 2′-deoxy-2′-fluoro-β-D-arabinopurinenucleoside from 2′-deoxy-2′-fluoro-β-D-arabinopyrimidinenucleoside and a purine base by use of a nucleoside phosphorylase (Patent Document 4).    Patent Document 1: WO99/67378 pamphlet    Patent Document 2: JP-B-H7-23395    Patent Document 3: JP-A-2002-205996    Patent Document 4: JP-A-S63-258891    Non-Patent Document 1: Biochemistry, 41, 3457 (2002)    Non-Patent Document 2: Bioorg. Med. Chem. Lett., 12, 2651, (2002)    Non-Patent Document 3: J. Org. Chem., 50, 3644 (1985)    Non-Patent Document 4: J. Org. Chem., 53, 85 (1988)